Orthostatic intolerance is the most frequently encountered dysautonomia and the cause of much disability. As many as 500,000 Americans are affected by it. Yet it is one of the least studied diseases. There is no established therapy. Its etiology is poorly understood, but is assumed to be heterogeneous. In this project, we propose a potential mechanism for orthostatic intolerance, which may represent the pathophysiology relevant to a significant portion or perhaps a majority of this patient population. We test the hypothesis that the subgroup of these patients have partial or distal dysautonomia, giving rise to a clinical syndrome of blood pooling, salt wasting, inadequate plasma volume, and attempted but inadequate compensation of a relatively intact proximal autonomic innervation of the heart. To prove that a partial or distal dysautonomia causes orthostatic intolerance in some patients, several criteria must be met. First, there must be evidence of local impairment in the sympathetic noradrenergic system, and this evidence should be based on biochemical, physiological and pharmacological criteria. Second, the impairment should be greater at distal (lower extremity) sites than at proximal (cardiac) sites. Third, central autonomic control should be preserved. Finally, denervation hypersensitivity should be greatest in the areas where the dysautonomia is most extensive. The unexpected finding that suppressed plasma renin levels occur in these patients, largely in direct proportion to the hypovolemia, and, in spite of orthostatic tachycardia and raised plasma norepinephrine levels, could be the crucial impairment that results in the hypovolemia. Since the initial submission, we have much new preliminary data congruent with our hypothesis (see figures 1,2,12,13 and the designated sections of text. Successful mechanistic characterization of this disorder should lead to improved diagnosis and the rational design of therapy in a significant portion of individuals presenting with previously unexplained pathological orthostatic intolerance.